Reye syndrome is characterized by hyperammonemia, elevated free fatty acids, and hepatic microvesicular fat deposition and swollen mitochondria. We have developed an animal model in which administration of a sublethal dose of endotoxin to fasted Sprague- Dawley rats produces biochemical and morphologic changes similar to Reye syndrome. Hepatic fatty acid metabolism is impaired in both endotoxemia and Reye syndrome yet the biochemical defect is unknown. Our working hypothesis is that in children who develop Reye syndrome there is an altered sensitivity and/or decreased capacity to clear endotoxin by the Reticuloendothelial system (RES). The increased sensitivity to endotoxin may be genetic or acquired and involve macrophage derived monokines. In this project: 1) we will biochemically characterize the metabolic derangements in hepatic aerobic energy production secondary to endotoxin and/or endotoxin and aspirin. We will study isolated hepatocytes and determine the rates of fatty acid oxidation, flux through the citric acid cycle, cellular oxygen consumption, cytosolic free calcium, and morphologic alterations. 2) We will determine the Reticuloendothelial System (RES) mechanisms which produce and modulate the effects of endotoxin. We will perform in vitro studies utilizing isolated rat Kupffer cells, monocyte derived macrophages, supernatants of monocyte- macrophage cultures and purified monokines in order to determine the mechanisms whereby macrophage secretory products and/or purified monokines alter hepatocyte biochemical functions. We will also examine the ability of fibronectin, a glycoprotein which modulates RES function, to alter these effects. The overall goal of this project is to determine the mechanisms by which endotoxin- macrophage interaction leads to production of monokines and/or other secretory products which cause altered hepatic aerobic energy production and hepatocellular damage similar to that which occurs in children with Reye syndrome.